Research Organizations

Research Summary

The majority of the work in my laboratory is currently focused on human genome diversity: the patterns of normal genetic variation among four dozen populations (~2500 individuals) from around the world, the variation in those patterns along the genome, and the inference of recent human evolutionary processes. The research involves both molecular and biostatistical components. Because of longstanding interest in neuropsychiatric disorders that fail to show a Mendelian pattern but do "run in families," our genome diversity studies include sequence variation at several genes with important neurologic functions, candidate genes for various neuropsychiatric disorders, and genes demonstrated to be associated with alcoholism. Managing these genotype and allele frequency data and making them publicly available has also involved us in a major bioinformatics effort: ALFRED, the allele frequency database we have developed. That database, illustrations of our human evolution findings, recent publications, and other material can be accessed through the Lab’s website.

Extensive Research Description

Normal DNA sequence variation such as single nucleotide
polymorphisms (SNPs), short tandem repeat polymorphisms (STRPs), etc.
have made Homo sapiens amenable to many types of genetic analysis. We
are using these polymorphisms to study the genes for several
inherited disorders, including neuropsychiatric disorders, and working
on statistical methods to analyze the data. We are studying these and other
polymorphisms genome-wide on DNA samples from many different human populations with
an emphasis on understanding the organization of normal variation
including studies of linkage disequilibrium and estimates of the
distribution of the variation in the entire species. We have
established a database, ALFRED, the ALelle FREquency Database, to
accumulate allele frequencies of DNA polymorphisms. A current focus is on forensic uses of SNPs.

For the past several years my laboratory has studied the genetics of
complex human disorders, those disorders that fail to show a Mendelian
pattern but do "run in families". DNA polymorphisms are now being used
to search for the genetic loci of major effect in behavioral and other
complex disorders. Our previous efforts focused on finding genes responsible for
neuropsychiatric disorders, especially Giles de la
Tourette Syndrome and schizophrenia. While no locus
appears to account for all cases of Tourette Syndrome, we have
strong evidence of a predisposing genetic factor on the distal long arm
of chromosome 17. Studies are ongoing through collaborations to narrow the region and identify
the relevant variant.

We are studying the population genetics of expressed and
non-expressed genetic variation at several genes of known neurologic
relevance, such as the dopamine receptors D2 and D4 and the enzyme
COMT, Catechol-O-methyl transferase. Also, because of their
demonstrated relevance to alcoholism we are studying the genes involved
in ethanol metabolism, the ADH genes and ALDH2. Understanding the
nature of the common normal variation at these loci provides a
background for investigating how they might influence normal and
abnormal neurologic/metabolic function and susceptibility to
psychiatric disorders. The duplicated ADH Class 1 genes are unique to
primates and are the focus of molecular evolution studies.
Several more evolution-oriented projects are also being pursued.
These include theoretical studies as well as studying samples from
diverse human populations for DNA polymorphisms. For some genes of
interest we are also collecting DNA sequence of other great apes to
examine the origins of the human lineage.

The lab's efforts are
currently focused on genome diversity among world populations and
understanding how that diversity arose. We have accumulated cell lines
on individuals from over 45 different populations and plan to increase
this resource in the coming years. On a global basis we are finding
that the majority of alleles for nuclear DNA polymorphisms are present
in most populations around the world, though sub-Saharan African
populations have more genetic variation (alleles), in general, than
indigenous populations in any other part of the world. We interpret the
data to mean that there was a major founder effect and loss of
variation associated with the expansion of modern humans out of Africa.
Haplotype data collected on all of the populations we are studying are
beginning to reveal patterns that provide a better understanding of
that founder effect and the recent evolutionary history of modern
humans. Recent studies have used these resources to select SNPs that
can be useful in forensics, both for individual identification
(matching the DNA at a crime scene with a suspect's DNA). Other SNPs
are being selected for their value in inference of ancestry from an
individual's DNA.

Bioinformatics research, in collaboration with the Yale Center for
Medical Informatics, is ongoing in two areas. We are working to improve
data management for the extensive marker typing results accumulating on
many of the projects. We are also working to improve the utility of
data in ALFRED through new search and display modes as well as relevant
links to other online sources

Gene study using polymorphism of the DNA for several inherited disorders

Collaborative study to narrow the region and identify the chromosome involved in Tourette syndrome and Schizophrenia

Population genetics of expressed and non-expressed genetic variation at several genes of known neurologic relevance

Bioinformatics research to improve data management for extensive marker typing results and improve the utility of data in ALFRED

Contact Info

Mailing Address

GeneticsPO Box 208005333 Cedar StreetNew Haven, CT06520-8005

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Department of Genetics

Yale University School of Medicine333 Cedar StreetNew HavenCT06520203.785.2649203.785.7227